Whether dietary omega-3 (or n-3) polyunsaturated fatty acids are causally related to risk of coronary heart disease (CHD) is a major, unresolved question in preventive cardiology. Essential n-3 fatty acids are eicosapentaenoic acid (EPA; C20:5,n-3) and docosahexaenoic acid (DHA; C22:6,n-3) on one hand, and their parent compound alpha-linolenic acid (ALA; C18:3, n-3) on the other hand. The intake of n-3 fatty acids is below recommended levels in most Western populations. The Alpha Omega Trial is a randomized, double-blind, placebo-controlled study of the effect of low-dose supplementation of ALA and EPA-DHA on coronary mortality. A total of 4000 Dutch men and women aged 60-80 years who had a myocardial infarction in the past 10 years are randomly allocated to 2 g/d of ALA, 400 mg/d of EPA-DHA, 2 g/d ALA + 400 mg/d EPADHA, or placebo, for 3 years. Increased intake of n-3 fatty acids is achieved through daily use of 20 g of margarine on bread. Margarines for all treatment groups are similar in taste and appearance. The primary outcome of the trial is fatal CHD. Secondary outcomes are cardiovascular disease mortality, sudden cardiac death and all-cause mortality. Complete follow-up for vital status is achieved. Cause-specific mortality is coded by an independent Endpoint Adjudication Committee. Physical examination, blood sampling and data collection on diet and lifestyle are performed in all subjects at baseline and after 3 y, and in 800 randomly selected subjects after 1.5 y of intervention. Cardiovascular health, serious adverse events, lifestyle, fish intake and margarine use are monitored in all subjects by yearly telephone interviews. Compliance is continuously monitored by a.o. registration of margarine tubs. An objective biomarker of compliance (i.e., plasma n-3 fatty acids) is obtained in 800 randomly selected subjects at baseline and after 1.5 and 3 y of intervention. The Alpha Omega Trial could provide a sound scientific basis for dietary recommendations on intake of ALA and EPA-DHA, in order to reduce CHD both in high-risk subjects and the general population.